Drug disposition alterations in liver disease: extrahepatic effects in cholestasis and nonalcoholic steatohepatitis.
Drug disposition alterations in liver disease: extrahepatic effects in cholestasis and nonalcoholic steatohepatitis.
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DOI：
10.1517/17425255.2014.936378
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发表时间：
2014-09
影响因子：
4.3
通讯作者：
Cherrington NJ
中科院分区：
文献类型：
--
作者：
Canet MJ;Cherrington NJ
药物和异生素（即药物）的药代动力学受到许多因素的影响，包括遗传、生理因素和环境应激源。医学专业人士越来越认识到疾病对外源物质处置的重要性，因为影响药物处置并导致药物不良反应发生的关键酶和膜转运蛋白的改变。本综述将调查有关肝病如何改变药物和其他外源性药物的药代动力学的相关文献。重点是非酒精性脂肪性肝炎和胆汁淤积性肝病。将回顾基本药代动力学原理，特别强调外源代谢酶和膜转运蛋白。具体来说，将重点介绍基因改变如何分别影响新陈代谢和排泄的例子。最后，将探讨“肝外”调节的想法，并举例说明肝脏中的疾病表现如何影响远端部位（例如肾脏）的药物分布。将提供专家意见，强调明确需要数据来了解肝病存在下膜转运蛋白的肝外调节及其显着改变多种药物和异生素的药代动力学和毒代动力学特征的潜力。
The pharmacokinetics of drugs and xenobiotics, namely pharmaceuticals, is influenced by a host of factors that include genetics, physiological factors, and environmental stressors. The importance of disease on the disposition of xenobiotics has been increasingly recognized among medical professionals for alterations in key enzymes and membrane transporters that influence drug disposition and contribute to the development of adverse drug reactions. This review will survey pertinent literature of how liver disease alters the pharmacokinetics of drugs and other xenobiotics. The focus will be on nonalcoholic steatohepatitis as well as cholestatic liver diseases. A review of basic pharmacokinetic principles, with a special emphasis on xenobiotic metabolizing enzymes and membrane transporters will be provided. Specifically, examples of how genetic alterations affect metabolism and excretion, respectively, will be highlighted. Lastly, the idea of “extra-hepatic” regulation will be explored, citing examples of how disease manifestation in the liver may affect drug disposition in distal sites, such as the kidney. An expert opinion will be provided highlighting the definite need for data in understanding extra-hepatic regulation of membrane transporters in the presence of liver disease and its potential to dramatically alter the pharmacokinetic and toxicokinetic profile of numerous drugs and xenobiotics.